A common side effect of an illness such as an infection is appetite suppression, which can quickly lead to malnutrition. Because malnutrition extends hospital stay, increases costs and exacerbates mortality, nutritional support (NS) is instituted. Unfortunately hyperglycemia is common in infected individuals and hyperglycemia negatively impacts on morbidity and mortality. We discovered that in healthy subjects the liver and muscle adapt to sustained NS by increasing their capacity to take up and oxidize glucose. As glucose is a major caloric source in NS, this adaptation is essential to minimize hyperglycemia. Infection impairs this adaptive response to NS and the current therapy administration of exogenous insulin cannot reverse this impairment. We also discovered in response to NS plasma glucagon decreases and liver derived and plasma FGF-21 increase. In addition if glucagon is increased as occurs with an infection, hepatic FGF-21 and plasma FGF-21 decrease and both hepatic and muscle carbohydrate oxidation are decreased. As FGF-21 is known to augment tissue glucose uptake our hypothesis is that, during NS, infection induced hyperglucagonemia limits FGF-21 availability and that together these changes attenuate tissue glucose uptake. We will use state of the art tracer and controlled metabolic studies to assess glucose and lipid flux in healthy and infected animals.
In Aim 1 we will determine if glucagon mediated suppression of hepatic FGF-21 secretion is responsible for the decrease in muscle glucose uptake and determine whether Gs and/or Gq dependent signaling (using designer receptor technology) in the liver can explain the glucagon-mediated decrease in muscle glucose uptake.
In Aim 2 we will determine if antagonizing glucagon can reverse the infection-induced impairment in tissue glucose uptake during NS. We will also determine if liver derived FGF-21 serves a protective role during infection and whether replacement of FGF-21 can sustain tissue glucose uptake during infection.

Public Health Relevance

Hyperglycemia negatively impact outcomes in infected patients receiving nutritional support. A major cause of the hyperglycemia during an infection is a failure of the liver and muscle to adapt to nutritional support and take up glucose more efficiently. This proposal will determine the role glucagon and FGF-21 have in this response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK043748-22A1
Application #
8964249
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Teff, Karen L
Project Start
1992-02-01
Project End
2019-04-30
Budget Start
2015-07-01
Budget End
2016-04-30
Support Year
22
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
Rossi, Mario; Zhu, Lu; McMillin, Sara M et al. (2018) Hepatic Gi signaling regulates whole-body glucose homeostasis. J Clin Invest 128:746-759
Boortz, Kayla A; Syring, Kristen E; Pound, Lynley D et al. (2017) Effects of G6pc2 deletion on body weight and cholesterol in mice. J Mol Endocrinol 58:127-139
Boortz, Kayla A; Syring, Kristen E; Dai, Chunhua et al. (2016) G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress. Endocrinology 157:3002-8
Syring, Kristen E; Boortz, Kayla A; Oeser, James K et al. (2016) Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion. Endocrinology 157:4534-4541
Dooley, James; Garcia-Perez, Josselyn E; Sreenivasan, Jayasree et al. (2016) The microRNA-29 Family Dictates the Balance Between Homeostatic and Pathological Glucose Handling in Diabetes and Obesity. Diabetes 65:53-61
Boortz, Kayla A; Syring, Kristen E; Lee, Rebecca A et al. (2016) G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance. Endocrinology 157:4133-4145
Otero, Yolanda F; Mulligan, Kimberly X; Barnes, Tammy M et al. (2016) Enhanced Glucose Transport, but not Phosphorylation Capacity, Ameliorates Lipopolysaccharide-Induced Impairments in Insulin-Stimulated Muscle Glucose Uptake. Shock 45:677-85
House 2nd, Lawrence M; Morris, Robert T; Barnes, Tammy M et al. (2015) Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance. Cardiovasc Diabetol 14:56
Kolumam, Ganesh; Chen, Mark Z; Tong, Raymond et al. (2015) Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/?Klotho Complex. EBioMedicine 2:730-43
Cyphert, Travis J; Morris, Robert T; House, Lawrence M et al. (2015) NF-?B-dependent airway inflammation triggers systemic insulin resistance. Am J Physiol Regul Integr Comp Physiol 309:R1144-52

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